The invention relates to substituted norbornylamino derivatives having exo-configured nitrogen and an endo-fused five-, six- or seven-membered ring of the formula I, or having exo-configured nitrogen and an exo-fused five-, six- or seven-membered ring of the formula I a 
in which:
A is (C1-C4)-alkylene;
S1 is a free electron pair or (C1-C4)-alkyl;
S2 is (C1-C4)-alkyl or H;
where, if S1 and S2 are alkyl, X in the resulting grouping [xe2x80x94N+(S1S2)-Xxe2x88x92] corresponds to a pharmacologically acceptable anion or trifluoroacetate;
B is a saturated or unsaturated five-, six- or seven-membered carbon ring which may be mono- or, independently of one another, polysubstituted by oxo, hydroxyl, (C1-C4)-alkoxy and (C1-C4)-alkyl; and
R1, R2, R3, R4 and R5 are, independently of one another, H, OH, F, Cl, Br, I, CN, NO2, amidino, xe2x80x94CO2R(11), xe2x80x94CONR(11)R(12), xe2x80x94SOrR(11), xe2x80x94SOsNR(11)-R(12), (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyloxy, hydroxy-(C1-C4)-alkyl, (C3-C7)-cycloalkoxy or phenyloxy,
where phenyl is unsubstituted or substituted by up to three substituents, which are independent of one another and selected from the group consisting of F, Cl, Br and methoxy;
amino, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, amino-(C1-C4)-alkyl, di-(C1-C4)-alkylamino-(C1-C4)-alkyl, (C1-C4)-alkylamino-(C1-C4)-alkyl,
where some or all of the hydrogen atoms in the alkyl radicals may be substituted by fluorine;
R11 and R12 are, independently of one another, H or (C1-C4)-alkyl, where some or all of the hydrogen atoms in the alkyl radicals may be substituted by fluorine;
r is 0, 1 or 2;
s is 1 or 2; or
R1 and R2, R2 and R3, R3 and R4 or R4 and R5 in each case together are a group xe2x80x94Oxe2x80x94(CH2)nxe2x80x94Oxe2x80x94;
n is 1 or 2; and
the radicals R1, R2, R3, R4 or R5 which remain in each case are, independently of one another, H, OH, F, Cl, Br, I, CN, NO2, amidino, xe2x80x94CO2R(11), xe2x80x94CONR(11)R(12), xe2x80x94SOrR(11), xe2x80x94SOsNR(11)-R(12), (C1-C4)-alkyl, (C1-C4)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C7)-cycloalkoxy, hydroxy-(C1-C4)-alkyl, amino, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, amino-(C1-C4)-alkyl, di-(C1-C4)-alkylamino-(C1-C4)-alkyl, (C1-C4)-alkylamino-(C1-C4)-alkyl, where some or all of the hydrogen atoms in the alkyl radicals may be substituted by fluorine;
R11 and R12 are, independently of one another, H or (C1-C4)-alkyl, where some or all of the hydrogen atoms in the alkyl radicals may be substituted by fluorine;
r is 0, 1 or2;
s is 1 or 2;
except for benzyl(octahydro-4,7-methanoinden-5-yl)amine,
and their pharmaceutically acceptable salts or trifluoroacetates.
Preference is given to compounds having exo-configured nitrogen and an endo-fused five- or six-membered ring of the formula I, or having exo-configured nitrogen and an exo-fused five- or six-membered ring of the formula I a, in which:
A is (C1-C2)-alkylene;
S1 is a free electron pair or methyl;
S2 is H;
B is a saturated or unsaturated five- or six-membered carbon ring;
R1, R2, R3, R4 and R5 are, independently of one another, H, amino, hydroxymethyl, OH, methoxy, F, Cl, Br or iodine; or
R2 and R3 together are xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94; and
the remaining radicals R1, R4 and R5 are, independently of one another, H, OH, F, Cl, Br, I, CN, NO2, (C1-C2)-alkoxy, amino, (C1-C2)-alkylamino or di-(C1-C2)-alkylamino, where some or all of the hydrogen atoms in the alkyl radicals may be substituted by fluorine;
except for benzyl(octahydro-4,7-methanoinden-5-yl)amine,
and their pharmaceutically acceptable salts or trifluoroacetates.
Particular preference is given to compounds having exo-configured nitrogen and an endo-fused five- or six-membered ring of the formula I, or having exo-configured nitrogen and an exo-fused five- or six-membered ring of the formula I a, in which:
A is (C1-C2)-alkylene;
S1 is a free electron pair;
S2 is H;
B is a saturated or unsaturated five- or six-membered carbon ring;
R1, R3 and R5 are hydrogen;
and R2 and R4 are, independently of one another, H, methoxy, F or Cl; or
R2 and R3 together are xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94; and
R1, R4 and R5 are hydrogen;
except for benzyl(octahydro)-4,7-methanoinden-5-yl)amine,
and their pharmaceutically acceptable salts or trifluoroacetates.
Very particular preference is given to the following compounds, having exo-configured nitrogen and an endo-fused five- or six-membered ring of the formula I, or having exo-configured nitrogen and an exo-fused five-membered ring of the formula I a:
exo/endo-(3-chlorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(3-fluorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-benzo[1,3]dioxol-5-ylmethyl(octahydro-4,7-methanoinden-5-yl)-amine,
exo/endo-(rac)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)-amine,
exo/endo-(+)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(xe2x88x92)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-[1-(3-methoxyphenyl)ethyl](octahydro-4,7-methanoinden-5-yl)-amine,
exo/endo-(3-fluorobenzyl)(3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)amine,
exo/endo-(3-fluorobenzyl)(3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)amine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)(3-methoxybenzyl)amine,
exo/endo-(3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)(3-methoxybenzyl)amine,
exo/endo-(decahydro-1,4-methanonaphthalen-2-yl)(3-methoxybenzyl)-amine,
exo/endo-(3,5-difluorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/exo-(3-fluorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine, and
exo/exo-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
and their pharmaceutically acceptable salts or trifluoroacetates.
Most particular preference is given to the following compounds, having exo-configured nitrogen and an endo-fused five- or six-membered ring of the formula I:
exo/endo-(3-chlorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(3-fluorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(3-fluorobenzyl)(3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)amine,
exo/endo-(3-fluorobenzyl)(3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)amine,
exo/endo-benzo[1,3]dioxol-5-ylmethyl(octahydro-4,7-methanoinden-5-yl)-amine,
exo/endo-(rac)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(+)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
exo/endo-(decahydro-1,4-methanonaphthalen-2-yl)(3-methoxybenzyl)-amine,
exo/endo-(xe2x88x92)-(3-methoxybenzyl)(octahydro-4,7-methanoinden-5-yl)amine, and
exo/endo-(3,5-difluorobenzyl)(octahydro-4,7-methanoinden-5-yl)amine,
and their pharmaceutically acceptable salts or trifluoroacetates.
Suitable acid addition salts are the salts of all pharmacologically acceptable acids, for example halides, in particular hydrochlorides, lactates, sulfates, citrates, tartrates, acetates, phosphates, methylsulfonates, p-toluene-sulfonates, adipates, fumarates, gluconates, glutamates, glycerol phosphates, maleates, and pamoates. This group also corresponds to the pharmacologically acceptable anions. However, trifluoroacetates are also suitable.
If the compound of the formula I or Ia contains one or more centers of asymmetry, these can be either S- or R-configured. The compounds can be present as optical isomers, diastereomers, racemates, or mixtures thereof. However, the amino substituent has to be in the exo position and the ring has to be endo- and exo-fused, respectively.
The alkyl or alkylene radicals mentioned can be straight-chain or branched.
The invention furthermore relates to a process for preparing the compounds of the formula I or I a, which comprises
a) reacting a compound of the formula II or II a 
xe2x80x83with a compound of the formula III 
xe2x80x83in which S1, S2, B, R1, R2, R3, R4 and R5 are as defined above, while independently of one another Axe2x80x2 is a bond or (C1-C3)-alkylene and Axe2x80x3 is H or (C1-C3)-alkyl and Axe2x80x2 and Axe2x80x3 together with the carbon atom of the carbonyl group represent the same number of carbon atoms as A,
in the presence of suitable reducing agents and optionally also Lewis acids directly to give compounds of the formula I or I a; or
b) isolating the intermediate of the formula IV or IV a 
xe2x80x83formed from compounds of the formulae II or II a and III, in which, if S1 is (C1-C4)-alkyl, an onium nitrogen is formed which is associated with a counterion, such as, for example, chloride or tosylate,
and then converting the intermediate with suitable reducing agents into the compounds of the formula I or Ia; or
c) reacting a compound of the formula II or II a with an alkylating agent of the formula V 
xe2x80x83in which U is a nucleophilically substitutable groupxe2x80x94such as chlorine, bromine and iodine and also mesylate, tosylate or triflate or another good leaving groupxe2x80x94and the other radicals are as defined above, but where the carbon atom to which U is attached corresponds to the carbon atom of the carbonyl group,
preferably in the presence of non-nucleophilic bases, such as diisopropyl-ethylamine; or
d) reducing carboxamides of the formula VI or VI a 
xe2x80x83in which A* is a bond or (C1-C3)-alkylene and the other radicals are as defined above
to give the corresponding amines; or
e) mono- or dialkylating compounds of the formula I or Ia in which S1 is a free electron pair and S2 is hydrogen, with alkylating agents of the formula VII
S*xe2x80x94Uxe2x80x83xe2x80x83VII
xe2x80x83in which S* is (C1-C4)-alkyl and U is as defined above, thus obtaining tertiary amines or quaternary ammonium salts; or
f) reacting a dicyclopentadienylplatinum complex of the formula VIII 
with amines of the type of the formula IX 
xe2x80x83in which S1, S2, R1, R2, R3, R4 and R5 are as defined above, while independently of one another Axe2x80x2 is a bond or (C1-C3)-alkylene and Axe2x80x3 is H or (C1-C3)-alkyl and Axe2x80x2 and Axe2x80x3 together with the carbon atom to which the nitrogen atom is attached represent the same number of carbon atoms as A,
and then reducing the intermediate formed to give compounds of the formula I (J. K. Stille, D. B. Fox JACS 1970 (92), 1274);
optionally followed by conversion into the pharmaceutically acceptable salt or trifluoroacetate.
U.S. Pat. No. 4,024,274 (Hoe 74/F018) describes norbornylamines having a similar type of structure, but an unknown steric structure, which have good diuretic and saluretic activity.
During screening of the large number of examples given in that patent, it was surprisingly found that some compounds of this type of structure are potent inhibitors of the sodium/proton exchanger, subtype 3 (NHE3). The most potent compound was then examined for its salidiuretic activity and, surprisingly, it was not possible to demonstrate any salidiuretic activity, so that a connection between NHE3 activity and salidiuresis could not be shown.
Since the steric structure of the tricycle was unknown, there was a choice between four possible pairs of enantiomers, i.e., a total of eight sterically different structures. For these pairs of enantiomers, it was found that only two pairs have a potent NHE3-inhibiting activity, whereas the other two pairs of enantiomers have hardly any NHE3-blocking properties. Elucidation of the most active structure by X-ray analysis showed that the most highly NHE3-active pair of enantiomers are compounds having a defined exo-configuration for the nitrogen and a defined endo-fused five-membered ring. The pair of enantiomers which is slightly less active has the defined exo-configuration for the nitrogen and a defined exo-fused five-membered ring. The two remaining pairs of enantiomers having defined endo/exo and endo/endo configuration, respectively, show hardly any NHE3-inhibiting activity.
Furthermore, it was surprising that the defined separated enantiomers of one of the exemplary compounds having the defined exo-configuration for the nitrogen and the defined endo-fused five-membered ring were both of similar activity at the NHE3. Owing to their enantiomeric steric arrangement, a considerable difference in activity was expected here.
With respect to the known inhibitors of the sodium/proton exchanger, subtype 3, according to EP-A 825 178 (HOE 96/F226), which represent relatively polar structures and correspond to the acylguanidine type (J.-R. Schwark et al. Eur. J. Physiol (1998) 436:797), the compounds according to the invention are surprisingly lipophilic substances which are not of the acylguanidine type and which represent entirely novel structures for the inhibition of NHE3. According to our searches, they are, after the acylguanidines just mentioned and the delayed acting squalamine (M. Donowitz et al. Am. J. Physiol. 276 (Cell Physiol. 45): C136-C144; activity seen after one hour) only the third class of substances of NHE3 inhibitors which has hitherto been disclosed. Compared with the abovementioned known NHE3 inhibitors, they are better able to cross membranes and show no delay of their inhibitory effect.
The NHE3 is found in the body of various species, preferably in the gall bladder, the intestine, and the kidney (Larry Fliegel et al., Biochem. Cell. Biol. 76: 735-741, 1998), but it was also detected in the brain (E. Ma et al. Neuroscience 79: 591-603).
The compounds of the formula I or I a according to the invention are suitable for use as antihypertensives for the treatment of primary and secondary hypertension.
Moreover, the compounds on their own or in combination with NHE inhibitors of other subtype specificity can protect organs which are acutely or chronically undersupplied with oxygen by reducing or preventing ischemically induced damage. They are thus suitable as medicaments, for example for surgical interventions (e.g., in kidney and liver organ transplantation, where the compounds can be used for the protection of the organs in the donor before and during removal, for the protection of removed organs, for example during treatment with or storage thereof in physiological bath fluids, and in the transfer to the recipient""s body) or acute or chronic kidney failure. Particularly advantageously, they can be employed for preventing ischemically induced damage to the intestine.
Corresponding to their protective action against ischemically induced damage, the compounds are potentially also suitable as medicaments for the treatment of ischemias of the nervous system, in particular of the CNS, where they are suitable, for example, for the treatment of stroke or of cerebral edema. Moreover, the compounds of the formula I or Ia according to the invention are likewise suitable for the treatment of forms of shock, such as, for example, of allergic, cardiogenic, hypovolemic, and of bacterial shock.
The compounds furthermore induce an improvement in the respiratory drive and are therefore used for the treatment of respiratory conditions in the following clinical conditions and illnesses: impaired central respiratory drive (for example central sleep apneas, sudden infant death, postoperative hypoxia), muscle-related respiratory disorders, respiratory disorders after long-term respiration, respiratory disorders during adaptation in high mountain regions, obstructive and mixed forms of sleep apneas, acute and chronic lung diseases with hypoxia and hypercapnia.
Additionally, the compounds increase the muscle tone of the upper respiratory tract, thus suppressing snoring.
A combination of an NHE inhibitor with a carboanhydrase inhibitor (for example acetazolamide), the latter producing a metabolic acidosis and thereby even increasing respiratory activity, proves to be a favorable combination with increased action and decreased use of active compound.
It has been found that the compounds according to the invention have a mild laxative effect, and they can therefore advantageously be used as laxatives or for imminent bowel obstruction, where the prevention of ischemic damage associated with obstruction in the intestinal area is particularly advantageous.
It is furthermore possible to prevent formation of biliary calculus.
The compounds of the formula I or Ia according to the invention may additionally have an inhibiting effect on the proliferation of cells, for example fibroblast cell proliferation and the proliferation of vascular smooth muscle cells. The compounds of the formula I or Ia are therefore suitable as valuable therapeutics for illnesses in which cell proliferation is a primary or secondary cause, and can therefore be used as antiatherosclerotics and as agents against late diabetic complications, carcinomatous disorders, fibrotic disorders, such as pulmonary fibrosis, hepatic fibrosis, or renal fibrosis, endothelial dysfunction, and organ hypertrophies and hyperplasias, in particular prostate hyperplasia or prostate hypertrophy.
The compounds according to the invention are effective inhibitors of the cellular sodium/proton antiporter, which is raised in numerous disorders (essential hypertension, atherosclerosis, diabetes, etc.) even in those cells which are easily accessible to measurements, such as, for example, in erythrocytes, platelets, or leucocytes. The compounds according to the invention are therefore suitable as outstanding and simple scientific tools, for example in their use as diagnostics for the determination and differentiation of certain forms of hypertension, but also of atherosclerosis, of diabetes, proliferative disorders, etc. Moreover, the compounds of the formula I or I a are suitable for preventive therapy for preventing the genesis of high blood pressure, for example, of essential hypertension.
It has additionally been found that NHE inhibitors have a favorable influence on the serum lipoproteins. It is generally recognized that the formation of arteriosclerotic vascular changes, in particular of coronary heart disease, excessively high blood lipid values, so-called hyperlipoproteinemias, are a significant risk factor. The lowering of raised serum lipoproteins is therefore of extreme importance for the prophylaxis and regression of atherosclerotic changes. The compounds according to the invention can therefore be used for the prophylaxis and for the regression of atherosclerotic changes, in that they exclude a causal risk factor. With this protection of the vessels against the endothelial dysfunction syndrome, the compounds of the formula I or I a are valuable medicaments for the prevention and for the treatment of coronary vasospasms, atherogenesis and atherosclerosis, left-ventricular hypertrophy and dilated cardiomyopathy, and thrombotic disorders.
The compounds mentioned are therefore used advantageously for the production of a medicament for the prevention and treatment of sleep apneas and muscle-related respiratory disorders; for the production of a medicament for the prevention and treatment of snoring; for the production of a medicament for lowering blood pressure; for the production of a medicament having a laxative effect for the prevention and treatment of intestinal obstructions; for the production of a medicament for the prevention and treatment of disorders caused by ischemia and reperfusion of central and peripheral organs and limbs, such as acute kidney failure, stroke, endogenous states of shock, intestinal disorders, etc.; for the production of a medicament for the treatment of hypercholesterolemia; for the production of a medicament for the prevention of atherogenesis and atherosclerosis; for the production of a medicament for the prevention and treatment of diseases caused by elevated cholesterol levels; for the production of a medicament for the prevention and treatment of diseases caused by endothelial dysfunction; for the production of a medicament for the treatment of infestation by ectoparasites; and for the production of a medicament for the treatment of the illnesses mentioned in combinations with hypotensive substances, preferably with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists. A combination of an NHE inhibitor of the formula I or I a with a blood lipid level-lowering active compound, preferably with an HMG-CoA-reductase inhibitor (for example lovastatin or pravastatin), where the latter produces a hypolipidemic action and thereby increases the hypolipidemic properties of the NHE inhibitor of the formula I or I a, proves to be a favorable combination with increased action and decreased use of active compound.
The invention includes the administration of sodium/proton exchange inhibitors of the formula I or I a as novel medicaments for lowering increased blood lipid levels, and also the combination of sodium/proton exchange inhibitors with hypotensive and/or hypolipidemic medicaments.
Medicaments that contain a compound I or I a can be administered orally, parenterally, intravenously, rectally, or by inhalation, the preferred administration being dependent on the particular clinical picture of the disorder. The compounds I or I a can be used on their own or together with pharmaceutical auxiliaries, both in veterinary and in human medicine.
The person skilled in the art is familiar on the basis of his expert knowledge with auxiliaries, that are suitable for the desired pharmaceutical formulation. Besides solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound excipients, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, or colorants.
For an oral administration form, the active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers, or inert diluents, and are brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, or aqueous, alcohol, or oily solutions. Inert excipients that can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular corn starch. In this case preparation can take place either as dry or as moist granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod-liver oil.
For subcutaneous or intravenous administration, the active compounds are brought into solution, suspension, or emulsion, if desired, using the substances customary for this purpose, such as solubilizers, emulsifiers, or other auxiliaries. Possible solvents are, for example: water; physiological saline solution or alcohols, for example ethanol, propanol, glycerol; or sugar solutions, such as glucose or mannitol solutions; or alternatively a mixture of the various solvents mentioned.
Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions, or emulsions of the active compound of the formula I or I a in a pharmaceutically acceptable solvent, such as, in particular, ethanol or water, or a mixture of such solvents.
If required, the formulation can also contain other pharmaceutical auxiliaries, such as surfactants, emulsifiers, and stabilizers, and also a propellant. Such a preparation contains the active compound customarily in a concentration of from approximately 0.1 to 10, in particular from approximately 0.3 to 3, % by weight.
The dosage of the active compound of the formula I or I a to be administered and the frequency of administration depend on the potency and duration of action of the compounds used, additionally also on the nature and severity of the illness to be treated and on the sex, age, weight, and individual responsiveness of the mammal to be treated.
On average, the daily dose of a compound of the formula I or I a in the case of a patient of approximately 75 kg in weight is at least 0.001 mg/kg, preferably 1-10 mg/kg, to at most 100 mg/kg, of body weight. In acute episodes of the illnesses, even higher and especially more frequent doses may also be necessary, for example up to four individual doses per day. In particular on i.v. administration, for example in the case of an infarct patient in the intensive care unit, up to 200 mg per day may be necessary.
Experimental Section:
Description of the Synthesis of Some Amines:
Amine 1)
Synthesis of the exo/endo-configured octahydro-4,7-methanoinden-5-ylamine: 
a1) bis-(6-chloro-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)-diazene N,Nxe2x80x2-dioxide and isomers 
167 g of isoamyl nitrite were added to a mixture of 167 g of dicyclopenta-diene, 160 ml of glacial acetic acid and 160 ml of ethanol, and at xe2x88x9210xc2x0 C., 420 ml of a 15% strength solution of hydrogen chloride in ethanol were then added dropwise with stirring. The mixture was stirred at room temperature for a further 3 hours. 500 ml of diisopropyl ether were added, the mixture was stirred for a further 10 minutes, and the crystals were then filtered off. Virtually colorless crystals, mp. 177-178xc2x0 C.
b1) octahydro-4,7-methanoinden-5-ylamine
A suspension of 10 g of bis-(6-chloro-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)diazene N,Nxe2x80x2-dioxide, 60 ml of methanol and Raney nickel was hydrogenated at 100xc2x0 C. and under an H2 pressure of 100 atm for 10 hours. The catalyst was filtered off, the solvent was evaporated under reduced pressure using a rotary evaporator, the semicrystalline residue was mixed with water, and the mixture was made strongly alkaline by addition of 10 N NaOH. The mixture was extracted 3 to 4 times with methyl tert-butyl ether and the organic phases were dried over sodium sulfate, and the solvent was then distilled off and the oil was rectified under reduced pressure. Bp5mm 86-91xc2x0 C. or
a2) 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-ylamine and 3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-ylamine 
20 g of exo-5-isothiocyanato-5,6-dihydroendodicyclopentadiene (Maybridge International) were dissolved in 60 ml of formic acid, and the solution was boiled under reflux for 27 hours. The volatile components were removed under reduced pressure, 50 ml of a 20% strength aqueous NaOH solution were added, and the mixture was extracted three times with, in each case, 100 ml of CH2Cl2. The extracts were dried over MgSO4 and the solvent was removed under reduced pressure. This gave 13.4 g of a pale yellow oil.
Rf(CH2Cl2/MeOH/HOAc/H2O 32:8:1:1)=0.57; MS (ES+): 150 (M+H)+
b2) tert-butyl (3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)-carbamate and tert-butyl (3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)carbamate
12.8 g of a mixture of 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-ylamine and 3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-ylamine were dissolved in 200 ml of THF and, at RT, admixed with a solution of 18.7 g of di-tert-butyl dicarbonate in 200 ml of THF. 12 ml of triethylamine were then added dropwise, and the mixture was stirred at RT for 2 hours. The volatile components were removed under reduced pressure and the residue was chromatographed over silica gel using DIP. This gave 15 g of a colorless oil which was crystallized from n-heptane; mp 94xc2x0 C.
Rf(DIP)=0.68 MS (Cl+): 250 (M+H)+
c2) tert-butyl (octahydro-4,7-methanoinden-5-yl)carbamate
500 mg of a mixture of tert-butyl (3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)carbamate and tert-butyl (3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-yl)carbamate were dissolved in 20 ml of methanol and 2 ml of acetic acid and hydrogenated under an atmosphere of hydrogen (1 bar) for 6 hours, with the aid of 200 mg of Pd/C 10% (50% water). The catalyst was filtered off and the volatile components were removed under reduced pressure. This gave 470 mg of a resin-like amorphous solid.
Rf(DIP)=0.70 MS (Cl+): 252 (M+H)+
d2) octahydro-4,7-methanoinden-5-ylamine trifluoroacetate
460 mg of tert-butyl (octahydro-4,7-methanoinden-5-yl)carbamate were dissolved in 5 ml of trifluoroacetic acid, and the mixture was stirred at RT for 24 hours. The volatile components were then removed under reduced pressure, giving 390 mg of a pale yellow foam.
Rf(EA/HEP/MeOH/CH2Cl2/saturated aqueous NH3 solution 10:5:5:5:1)=0.30
MS (Cl+): 152 (M+H)+or
a3) octahydro-4,7-methanoinden-5-ylamine
3.3 g of a mixture of 3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-ylamine and 3a,4,5,6,7,7a-hexahydro-3H-4,7-methanoinden-5-ylamine (example Amine 1, a2) were dissolved in 30 ml of methanol and reduced under an atmosphere of hydrogen in the presence of 0.5 g Pd/C (10%). After 4 hours the catalyst was filtered off and washed with methanol. The filtrate was concentrated in vaccuo to give 3 g of the desired product as an oil.
MS (ES+): 152 (M+H)+
Amine 2)
Synthesis of the endolexo-configured octahydro-4,7-methanoinden-5-yl-amine: 
A solution of 15 g of tricyclo[5,2,1,02,6]decan-8-one in 60 ml of methanol, which had been saturated beforehand at 10xc2x0 C. with NH3, was, after addition of Raney nickel, hydrogenated in an autoclave at 90xc2x0 C. and a hydrogen pressure of 100 bar for 10 hours. The catalyst was filtered off and the solvent was distilled off under reduced pressure, and the mixture was then made strongly alkaline using 10 N NaOH and extracted 2-3 times with ethyl acetate or with diisopropyl ether. The combined organic phases were dried and subjected to fractional distillation under reduced pressure. Bp6-7mm 86-88xc2x0 C.
Amine 3)
Synthesis of the endo/endo-configured octahydro-4,7-methanoinden-5-yl-amine: 
a) 1,3a,4,6,7,7a-hexahydro-4,7-methanoinden-5-one oxime
10 g of bis-(6-chloro-3a,4,5,6,7,7a-hexahydro-1H-4,7-methanoinden-5-yl)-diazene N,Nxe2x80x2-dioxide from amine 1, a1) were suspended in 75 ml of isoamyl alcohol, and the suspension was slowly heated to reflux with stirring. Once everything had been dissolved, the mixture was cooled to room temperature using an ice bath, and 25 ml of dry ethanol, 12.5 ml of glacial acetic acid, and 6 g of zinc dust were added. The mixture was kept at reflux for 1 hour and then cooled, the zinc was filtered off, and the ethanol was evaporated under reduced pressure. The residue was stirred into 300 ml of ether and allowed to stand overnight. The ether was then decanted off from the precipitate and washed three times with sodium carbonate solution and twice with water. The organic phase was dried over magnesium sulfate and filtered, and the filtrate was then concentrated. Subsequent distillation under reduced pressure gave 3.3 g of an oil which was directly reacted further.
b) octahydro-4,7-methanoinden-5-ylamine
2.2 g of 1,3a,4,6,7,7a-hexahydro-4,7-methanoinden-5-one oxime were dissolved in 50 ml of methanol, and about 10% Raney nickel, dissolved in 50% water, was added. The mixture was hydrogenated at 100 bar and 100xc2x0 C. for 20 hours, the catalyst was then filtered off, and the solvent was evaporated under reduced pressure. The residue was taken up in ether and 6 N aqueous sodium hydroxide solution, the phases were separated, the aqueous phase was extracted three times with ether, the combined organic phases were dried with magnesium sulfate and filtered, and the filtrate was concentrated. This gave 1.8 g of a colorless oil which was purified by kugelrohr distillation. This gave 0.96 g of the desired amine as an oil.
MS (Cl+): 152.2 (M+H)+
Amine 4)
Synthesis of the exo/exo-configured octahydro-4,7-methanoinden-5-yl-amine: 
a) octahydro-4,7-methanoinden-5-ol
25 g of tricyclo[5.2.1.0 (2,6)]decan-8-one (Aldrich) were dissolved in 100 ml of methanol and, at room temperature and with slight cooling and stirring, admixed a little at a time with 6.3 g of solid sodium borohydride over a period of 2 h. The mixture was then stirred for another 2 h and allowed to stand overnight. With cooling, about 40 ml of 2 N HCl were then added dropwise, followed by 20 ml of water. The mixture was concentrated, the residue was admixed with ethyl acetate, and the ethyl acetate phase was washed once with water and once with sodium bicarbonate solution. The ethyl acetate phase was dried using magnesium sulfate and then filtered and concentrated. This gave 26 g of an oil which was purified by distillation under reduced pressure. This gave 20.7 g of an oily liquid (bp0.5 76xc2x0 C.).
b) 2-(octahydro-4,7-methanoinden-5-yl)isoindole-1,3-dione
With stirring, 1.7 g of diethyl azodicarboxylate, diluted with 5 ml of THF, were added to a solution of 1.66 g of octahydro-4,7-methanoinden-5-ol, 1.47 g of phthalimide, and 2.62 g of triphenylphosphine in 15 ml of THF. The reaction mixture was allowed to stand overnight and then concentrated, the residue was stirred with ether, the precipitate was filtered off with suction, and the filtrate was concentrated. The residue was purified over silica gel using toluene. This gave 1.36 g of a yellow oil.
MS (Cl+): 282.2 (M+H)+
c) exo/exo-octahydro-4,7-methanoinden-5-ylamine
0.4 g of hydrazine hydrate were added dropwise to a solution of 1.12 g of 2-(octahydro-4,7-methanoinden-5-yl)isoindole-1,3-dione and 15 ml of ethanol, and the mixture was stirred at 65xc2x0 C. for 2 h. The pH was then adjusted to pH 1-2 using conc. HCl and admixed with 10 ml of ethanol, the precipitate was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC over RP-18 using acetonitrile/water (0.05% trifluoroacetic acid). Freeze-drying gave 567 mg of product as the trifluoroacetate. Treatment with aqueous sodium hydroxide solution and ethyl acetate gave 322 mg of the free amine.
MS (Cl+): 152.0 (M+H)+